Successful host defense against viral infection, relies on the early detection of the virus followed by the rapid production of type IIFN genes and the establishment of a cellular anti-viral state. Detection is mediated by germline-encoded innate immune receptors, often referred to as pattern recognition receptors (PRRs). These PRRs, which include both TLRs (TLR3, TLR7, TLR8 and TLR9) and cytoplasmic RNA helicases (RIG-I, Mda-5 and possibly others) are capable of detecting viral nucleic acids. Double stranded RNA, a key signature of viral replication is recognised by TLRS, in the endosomal compartment, or by the RNAhelicases, if in the cytoplasm. Type I IFNgene induction downstream of TLRS and RIG-I requires the signal-dependent phosphorylation of IRF3, enabling IRF3 to dimerize, translocate to the nucleas and activate IFN gene transcription. TBK-1 and IKKE phosphorylate and activate IRF3. TBK1 and IKKe are required for TLR and RNA helicase signaling. Little else is known however, about the molecular events that connect TLRs or RNA helicases with these kinases. Our goal is to understand in detail these molecular events. We will use a combination of biochemical, visual and molecular genetic approaches to understand how viral pathogens are recognized by the innate immune response during infection and how these PRR- pathways activate these kinases. Successful completion of these studies will help us understand the molecular mechanisms responsible for the innate immune sensing of viral pathogens. These studies are also vital for the rational design of therapeutic agents to enhance innate immunity in host defense against infectious pathogens. Since type I IFNs also occupy centre stage inthe pathogenesis of systemic and organ-specific autoimmune diseases including Systemic Lupus Erythematosus (SLE), a clearer understanding of the regulation of these important immune mediators will also be useful for the treatment of these and other related autoimmune diseases. In summary, defining these pathways in great detail will be important to allow us to design therapies which could be used to turn on these kinases, as a way to assist in clearance of a viral pathogen, which would be advantageous to the host, or alternatively, to turn them off in situations, such as autoimmune disease, where production of IFN is disadvantageous to the host.